http://cs273a.stanford.edu [Bejerano Spr06/07] 1

TTh  11:00-12:15 in Clark S361

Profs: Serafim Batzoglou, Gill Bejerano

TAs: George Asimenos, Cory McLean

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Lecture 14

Co-option: Case study to Survey

Course Project

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Genomic Distribution of Ultraconserved Elements

•exonic•non•possibly

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Looks Like A Novel Coelacanth Repeat

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Uniquely Abundant in Coelacanth

?

x

Upto 80%id between Coelacanth instances

and some human instances, inc uc.338.

100 diverged copies in a Gigabase

60 highly similar copies in a Megabase

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Repeats / obile Elements ("selfish DNA")

HumanGenome:

3*109 letters1.5%

knownfunction >50%

junk

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The LF SINE (for Lobefin Fish / “Living Fossil”)

Reconstructionout back

target siteduplications

not similar to any known repeat

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>360My Old and Going Strong

?

x

B

D

Upto 80%id between Coelacanth SINE

and some human instances, inc uc.338.

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Cis-reg & Ultra elements from obile Elements

[Yass is a small town in New South Wales, Australia.]

Co-option event, probably due to favorable genomic context

All other copies are destined to decay over time at a neutral rate

[Bejerano et al., Nature 2006]

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Exapted Into Which Cellular Roles?

?

xHuman instances cluster together, found <1Mb from 35 TFs (P<3*10-6).

No evidence for Transcription (Tx) as small RNAs,

no orientation preference in introns, not in antisense Tx.

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Instance 500kb Downstream of ISL1

ISL1 is a neuro-developmental gene, also expressed in testis.

Three previously known enhancers are conserved across vertebrates.

1Mb

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Repeat made Regulatory Region

Reporter GeneMinimal PromoterConservedElement

in situ

transgenic

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Co-option into Different Roles

repeat

proteincoding

generegulating

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Age old Hypothesis: Repeat to Rewire!

[Britten & Davidson, 1971]

[Davidson & Erwin, 2006]

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Elsewhere…

[Thornburg et al., Gene, 2006]

Screened repeat copies found in

all annotated human promoters

for many TF binding site matrices

Found many enrichments:…

…

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The Co-Optionome

transposition

event

functionalelements

quantify co-option

LF-SINE, DeuSINE, MER121, …

?

x

[Lowe, Bejerano & Haussler, PNAS, 2007]

?

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Computationally Driven Biology Simplified

casestudy

hypothesis

set

gene

raliz

esurvey

analy

ze

CSBIO

candidates

experiment

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How to Generalize?

?

x

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In Search of the Co Optionome

conserved repetitive

50%5% 20%1.5%

>100Mya

highly conserved non-coding

(think functional, regulatory)

>100Mya

mobile element

instances

[%age

of H.G]

10,000 elements!

1Mb, 0.04% H.G

50-489bp, avg 100bp

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Specimen

Alus

ZFPM2: Zinc Finger TF,

Regulator of GATA TFs.

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Co-options are from all Repeat Classes

1Mb

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Co-options correlate with gene deserts

genomewide

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Co-options show clear functional preferences

GO term enrichment for nearest gene to co-opted element:10-75 Development (and system devel, nervous sys devel, etc)

10-72 Transcription Regulator Activity (and related terms)

10-23 Cell Recognition (neuron recog, tyros kinas sign, cell adhesion, etc)

Densest co-option “clouds” in the human genome:

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Britten & Davidson redux

[Britten & Davidson, 1971]

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Example: The reelin pathway

En-1 binding sites. Similar phenomenon for Oct-1 (Pou2f1), SRY, v-Myb and YY1.

involved in neuronal

development and function.

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Particular Repeat Portions More Prone To Co-option

all instances

exapted instances only

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Compare to exonization

all instances

exapted instances only

in exonization:

polyA5’ 3’

polyT5’ 3’

required for

repeat life cycle

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Compare to exonization

all instances

exapted instances only

in exonization:

polyA5’ 3’

polyT5’ 3’

required for

repeat life cyclefound in most

alt-splice exons

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A Significant Minority of Putative Cis-Reg

At least 7.5% of

conserved non coding

born after opposum split

originate in exaptation

(0.3% of all repeat instances

born in this time period)

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Inconclusive Evidence

• “Clouds” of exaptation around genes sometimes have many instances of same type, sometimes one of each, sometimes some random mix in between.

• The most frequently co-opted portions of a repeat are no more enriched for GO terms or annotated pathways than the set of all co-options of that mobile element.

• Sequence-similar (sub) families of co-options are not more enriched for GO terms or pathways either.

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SummaryCo-option of interspersed repeats into regulatory rolesappears to be a force of nature to be reckoned with.

Some open questions:What functions do repeats co-opt into?How are they pre-disposed to take these on?Prove Brittten & Davidson: Have they really contributedsignificantly/triggered the formation of any gene circuitry?(enticing to think about clade specific traits: placenta, brain, …)

Some Implications:microarray experiments, eg, ChIP-chipfunctional dissections of locicomputational analysis & modeling of cis-reg network

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discuss projects